A conserved nuclear export complex coordinates transcripts for dopaminergic synaptogenesis and neuronal surviva

Summary Synaptic vesicle and active zone proteins are required for synaptogenesis. The molecular mechanisms for coordinated synthesis of these proteins are not understood. Using forward genetic screens, we identified the conserved THO nuclear export C omplex (THOC) as master regulator of presynapse development in C.elegans dopaminergic neurons. In THOC mutants, synaptic messenger RNAs are trapped in the nucleus, resulting in dramatic decrease of synaptic protein expression, near complete loss of synapses and compromised dopamine function. cAMP-responsive element binding protein (CREB) interacts with THOC to mark activity-dependent transcripts for efficient nuclear export. Deletion of the THOC subunit Thoc5 in mouse dopaminergic neurons causes severe defects in synapse maintenance and subsequent neuronal death in the Substantia Nigra compacta (SNc). These cellular defects lead to abrogated dopamine release, ataxia and animal death. Together, our results argue that nuclear export mechanisms can select specific mRNAs and be a rate-limiting step for synapse development and neuronal survival. Highlights Dopaminergic presynapses are severely impaired in thoc mutant worms and mice THOC specifically controls the nuclear export of synaptic transcripts CREB recruits THOC onto activity-dependent synaptic transcripts for efficient export Dopamine neurons in the SNc degenerate upon conditional knock-out of thoc5